Flonase

CLINICAL PHARMACOLOGY

Mechanism Of Action

Fluticasone propionate is a synthetic trifluorinated
corticosteroid with anti-inflammatory activity. Fluticasone propionate has been
shown in vitro to exhibit a binding affinity for the human glucocorticoid
receptor that is 18 times that of dexamethasone, almost twice that of
beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone
dipropionate, and over 3 times that of budesonide. Data from the McKenzie
vasoconstrictor assay in man are consistent with these results. The clinical
significance of these findings is unknown.

The precise mechanism through which fluticasone
propionate affects rhinitis symptoms is not known. Corticosteroids have been
shown to have a wide range of effects on multiple cell types (e.g., mast cells,
eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g.,
histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. In 7
trials in adults, FLONASE Nasal Spray has decreased nasal mucosal eosinophils
in 66% of patients (35% for placebo) and basophils in 39% of patients (28% for
placebo). The direct relationship of these findings to long-term symptom relief
is not known.

Pharmacodynamics

HPA Axis Effect

The potential systemic effects of FLONASE Nasal Spray on
the HPA axis were evaluated. FLONASE Nasal Spray given as 200 mcg once daily or
400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg
given in the morning. FLONASE Nasal Spray at either dosage for 4 weeks did not
affect the adrenal response to 6-hour cosyntropin stimulation, while both
dosages of oral prednisone significantly reduced the response to cosyntropin.

Cardiac Electrophysiology

A study specifically designed to evaluate the effect of
FLONASE on the QT interval has not been conducted.

Pharmacokinetics

The activity of FLONASE Nasal Spray is due to the parent
drug, fluticasone propionate. Due to the low bioavailability by the intranasal
route, the majority of the pharmacokinetic data was obtained via other routes
of administration.

Absorption

Indirect calculations indicate that fluticasone
propionate delivered by the intranasal route has an absolute bioavailability
averaging less than 2%. Trials using oral dosing of labeled and unlabeled drug
have demonstrated that the oral systemic bioavailability of fluticasone
propionate is negligible ( < 1%), primarily due to incomplete absorption and
presystemic metabolism in the gut and liver. After intranasal treatment of
patients with rhinitis for 3 weeks, fluticasone propionate plasma
concentrations were above the level of detection (50 pg/mL) only when
recommended doses were exceeded and then only in occasional samples at low
plasma levels.

Distribution

Following intravenous administration, the initial disposition
phase for fluticasone propionate was rapid and consistent with its high lipid
solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human
plasma proteins averaged 99%. Fluticasone propionate is weakly and reversibly
bound to erythrocytes and is not significantly bound to human transcortin.

Elimination

Following intravenous dosing, fluticasone propionate
showed polyexponential kinetics and had a terminal elimination half-life of
approximately 7.8 hours. The total blood clearance of fluticasone propionate is
high (average: 1,093 mL/min), with renal clearance accounting for less than
0.02% of the total.

Metabolism: The only circulating metabolite
detected in man is the 17β-carboxylic acid derivative of fluticasone
propionate, which is formed through the CYP3A4 pathway. This metabolite had
less affinity (approximately 1/2,000) than the parent drug for the
glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological
activity in animal studies. Other metabolites detected in vitro using cultured
human hepatoma cells have not been detected in man.

Excretion: Less than 5% of a radiolabeled oral
dose was excreted in the urine as metabolites, with the remainder excreted in
the feces as parent drug and metabolites.

Special Populations

Fluticasone propionate nasal spray was not studied in any
special populations, and no gender-specific pharmacokinetic data have been
obtained.

Ketoconazole: Coadministration of orally inhaled
fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily)
resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a
45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of
cortisol.